PROTECTION AGAINST ACETAMINOPHEN-INDUCED LIVER-INJURY IN-VIVO BY AN IRON CHELATOR, DEFEROXAMINE

Background: Recent data indicate that iron ions play a major role in l ipid peroxidation, a hepatotoxic effect of acetaminophen (APAP). Metho ds: We investigated whether an iron chelator, deferoxamine (DFO), can protect against APAP-induced liver injury in vivo in rats. Results: DF O diminished the increase in serum alanine aminotransferase (ALAT) in a dose-dependent manner after APAP administration and also reduced mor tality. Administration of 750 mg/kg APAP resulted in an increased ALAT (11,666 +/- 4633) after 8 h, and the mortality at 24 h was 88%. Pretr eatment with 200 mg/kg DFO for Ih significantly reduced ALAT (to 3406 +/- 894) and mortality (38%). DFO also attenuated histopathologic chan ges. Treatment with DFO depressed malondialdehyde formation by APAP wi thout inhibiting glutathione depletion in the liver or reducing covale nt binding of [H-3]APAP to liver proteins. Conclusions: These results indicate that the protective effect of DFO against APAP-induced liver injury may be attributable not to changes in APAP metabolism but to th e chelation of iron, which can catalyze the generation of active oxyge n species, in hepatocytes.